This study has been transitioned to CTIS with ID 2023-508443-40-00 check the CTIS register for the current data. Dual Primary Objectives:• To compare progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR) using…
ID
Source
Brief title
Condition
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
OS is one of the dual primary endpoints for the study; it is defined as the
time from randomization to the date of death due to any cause. Participants who
are alive will be censored at the date of last contact.
Secondary outcome
The following key secondary efficacy endpoint will be evaluated:
• PFS in NSQ population defined as per primary PFS endpoint
• PFS in CR/PR population defined as per primary PFS endpoint
• OS in NSQ population defined as per primary OS endpoint
• OS in the CR/PR population
• TTP in the CNS is defined as the time from the date of randomization until
the earliest date of documented PD in the CNS. CNS progression is defined as
progression in the CNS due to new CNS lesion or progression of baseline CNS
lesion, as assessed by BICR per RANO-BM criteria.
Secondary Efficacy Endpoints
The following secondary efficacy endpoints will be evaluated:
• PFS as assessed by the Investigator using RECIST v1.1
• PFS, per RECIST v1.1 based on BICR, and OS by PD-L1 status (PD-L1 TC <1% and
NE
versus >=1%)
• TTD, defined as the time from randomization to meaningful deterioration on a
composite
endpoint of dyspnea, chest pain, and cough, on the EORTC QLQ-LC13
• Change from baseline in the EORTC QLQ-C30 and EORTC QLQ-LC13 domains
Safety Analysis (Secondary and Exploratory Endpoints)
Safety will be evaluated based on the incidence of AEs, SAEs, and AESIs, the
incidence of treatment discontinuations, dose interruptions, and dose
reductions due to AEs, SAEs, or AESIs, changes in ECOG performance status,
changes in clinical laboratory results (hematology, chemistry, thyroid
function, and urinalysis), vital sign measurements, observations during
physical examination, and use of concomitant medications
Background summary
Development of more efficacious treatment options for patients with NSCLC
remains a high unmet need. Novel combination therapy regimens are needed with
acceptable safety profiles that deliver clinically meaningful improvement in
PFS and OS when administered in the maintenance setting for patients with
advanced/metastatic NSCLC whose disease did not progress with frontline
pembrolizumab/platinum-based therapy.
This study will evaluate the efficacy of niraparib in combination with
pembrolizumab in comparison to pembrolizumab plus placebo as maintenance
therapy in participants with Stage IIIB, IIIC or IV NSCLC (both squamous and
non-squamous histology) who have achieved SD, PR, or CR in response to standard
of care induction with 4 to 6 cycles of platinum doublet chemotherapy and
pembrolizumab. Patients with asymptomatic brain metastases (BM) will be allowed
to enrol in this study given the high potential of lung cancer patients to have
or develop BM during treatment. If the participant did not have a CNS magnetic
resonance imaging (MRI) at the beginning of standard of care induction therapy,
the presence of BM at first screening scan will not be considered evidence of
progression in the absence of other factors, such as new CNS symptoms.
Study objective
This study has been transitioned to CTIS with ID 2023-508443-40-00 check the CTIS register for the current data.
Dual Primary Objectives:
• To compare progression-free survival (PFS) as assessed by Blinded Independent
Central Review (BICR) using Response Evaluation Criteria in Solid Tumors
Version 1.1 (RECIST v1.1) of niraparib plus pembrolizumab versus placebo plus
pembrolizumab as maintenance therapy in the overall population.
• To compare overall survival (OS) of niraparib plus pembrolizumab versus
placebo plus pembrolizumab as maintenance therapy in the overall population.
Key Secondary Objectives:
• To evaluate and compare the time to progression (TTP) in the central nervous
system (CNS) as assessed by BICR using Response Assessment in Neuro-Oncology
Brain Metastases (RANO-BM) criteria
• To compare PFS as assessed by Blinded Independent Central Review (BICR) using
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) of
niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance
therapy in the nonsquamous (NSQ) population
• To compare PFS as assessed by Blinded Independent Central Review (BICR) using
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) of
niraparib plus pembrolizumab versus placebo plus pembrolizumab as maintenance
therapy in best response to standard of care induction chemotherapy with
complete and partial response (CR/PR) population
• To compare OS of niraparib plus pembrolizumab versus placebo plus
pembrolizumab as maintenance therapy in the NSQ population
• To compare OS of niraparib plus pembrolizumab versus placebo plus
pembrolizumab as maintenance therapy in the best response to standard of care
induction chemotherapy with CR/PR population
Secondary Objectives:
• To evaluate CNS PFS as assessed by BICR using RANO-BM
• To evaluate PFS as assessed by the Investigator using RECIST v1.1
• To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by programmed
cell deathligand
1 (PD-L1) status (PD-L1 tumor cells [TCs] <1% versus >=1%)
• To evaluate and compare time to deterioration in lung symptoms (TTD), defined
as time from randomization to meaningful deterioration on a composite endpoint
of dyspnea, chest pain, and cough, from the European Organisation for Research
and Treatment of Cancer Quality of Life
Questionnaire 13-item lung cancer-specific module (EORTC QLQ-LC13)
• To evaluate changes from baseline in health-related quality of life (HRQoL)
and symptoms as assessed by the European Organisation for Research and
Treatment of Cancer Quality of Life Questionnaire 30-item Core module (EORTC
QLQ-C30) and the EORTC QLQ-LC13 total and
domain scores
• To evaluate safety and tolerability in participants treated with niraparib
plus pembrolizumab compared to placebo plus pembrolizumab
• To describe the exposure of niraparib when given in combination with
pembrolizumab
Exploratory Objectives:
• To further evaluate safety and tolerability in participants treated with
niraparib plus pembrolizumab compared to placebo plus pembrolizumab
• To evaluate time from randomization to progression or death from any cause in
the absence of progression, whichever comes first, on subsequent anticancer
treatment following maintenance therapy (progression-free survival 2 [PFS2])
- To evaluate ORR and DOR as verified by BICR per RECIST v1.1 and RANO-BM in
participants with evidence of disease at baseline
• To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by homologous
recombination deficiency (HRD) status (positive or negative)
• To evaluate PFS as assessed by BICR using RECIST v1.1 and OS by tumor
mutational burden (TMB) status (high versus low)
• To evaluate frequency and severity of symptomatic adverse events (AEs) based
on the Patient-Reported Outcomes Version of the Common Term Criteria for
Adverse Events (PRO-CTCAE) and the Functional Assessment of Cancer Therapy -
General Population (FACT-GP5)
• To evaluate change from baseline in overall symptom severity on the Patient
Global Impression of Severity/Change (PGIS/PGIC)
• To evaluate change from baseline as assessed by the European Quality of Life
5-Dimensions 3-Level Scale (EQ-5D-3L)
• To explore the impact of niraparib exposure on efficacy and safety endpoints
• To evaluate circulating tumor DNA (ctDNA) burden in blood from baseline and
on-treatment samples
• To explore potential mechanisms of either de novo or treatment-emergent
resistance
- To explore the effect of statins on the efficacy of niraparib
Study design
Participants may be randomized directly after completing the standard of care
induction period or, under the Investigator*s discretion, they may use an
optional recovery period and be randomized within 6 weeks of the last dose of
chemotherapy. If the 6-week recovery period is used, pembrolizumab, in the
absence of chemotherapy, must continue in the cycle immediately following the
last cycle of standard of care induction and in accordance with standard
prescribing directions.
In order to be a candidate for this study, participants must have SD, PR, or
CR, as assessed by the Investigator per RECIST v1.1 criteria, following 4-6
cycles standard of care treatment. In addition, a tumor specimen must be
submitted for central PD-L1 testing and stratification.
For all participating EU countries (including UK), the Ventana PD-L1 SP263
assay will be performed at Q Squared Solutions laboratory in West Lothian,
Scotland, United Kingdom. The Ventana PD-L1 SP263 assay is CE-marked for its
analytical performance in formalin-fixed, paraffin-embedded (FFPE) tissue
specimens.
Participants who have achieved SD, PR, or CR following the standard of care
induction treatment and who meet all eligibility criteria will be randomized in
a 1:1 ratio to receive niraparib plus pembrolizumab or placebo plus
pembrolizumab as maintenance therapy. The proportion of participants with SD
will be carefully monitored at the time of randomization, and a cap will be
applied at SD enrolment threshold of 50% of total sample size to prevent the
proportion of participants entering the study to differ significantly from the
proportions observed in the KEYNOTE-189 and KEYNOTE-407 studies (approximately
35% to 40%).
Participants will be stratified by:
• histology (squamous versus non-squamous),
• PD-L1 status (TC <1%/NE versus >=1%), and
• best response to standard of care induction chemotherapy (CR/PR versus SD)
Participants will continue to receive their assigned treatment until
radiographic PD is documented (and reviewed by BICR), unacceptable toxicity,
death, withdrawal of consent, or becoming lost to follow-up, whichever comes
first.
Treatment with pembrolizumab will continue for up to a total maximum of 35
cycles from the beginning of standard of care induction therapy (ie,
approximately 92 weeks from randomization). Treatment with niraparib/placebo
will continue until radiographic PD or other treatment discontinuation
criterion is met, or for up to 3 years.
Follow-up assessments will occur as indicated in the Schedule of Activities
(Table 1) of the study protocol.
An Independent Data Monitoring Committee (IDMC) will be established to provide
independent review and assessment of the efficacy and safety data. An interim
safety analysis will be assessed by the IDMC when approximately 120
participants total across both treatment arms have completed at least 2 cycles
of maintenance therapy. IDMC periodic data safety reviews will be performed as
specified in the IDMC charter.
Approximately 650 participants are expected to be randomized in the study.
Intervention
Niraparib/Placebo:
Niraparib/placebo will be administered orally once daily (2-3 tablets)
throughout each 21-day cycle until radiographic PD or another treatment
discontinuation criterion is met, or for up to 3 years.
(Standard treatment)
Pembrolizumab:
Pembrolizumab will be administered in accordance with the product*s standard
prescribing instructions as an IV infusion over approximately 30 minutes each
21-day cycle for up to a maximum of 35 cycles from the beginning of standard of
care induction therapy.
Study burden and risks
Side effects considered very common (may affect more than 1 in 10 people):
Decrease in the number of blood platelets, the number of red blood cells, the
number of white blood cells, the number and the number of neutrophils
High blood pressure, the heart skipping beats or beating harder than usual,
painful and frequent urination (urinary tract infection), shortness of breath,
runny or stuffy nose, cough, headache, dizziness, feeling weak, lack of energy,
difficulty in sleeping, joint pain, back pain, stomach pain, indigestion,
feeling sick, vomiting , frequent watery stools, constipation and decreased
appetite.
These side effects are considered common (may affect up to 1 in 10 people):
Infection due to low white blood cell counts, bronchitis
fast heart beat
swelling of lower legs and feet (edema)
muscle pain
rash, decrease in weight
feelings of sadness
depressed, feelings of worry
nervousness or unease
inflammation of the eye (conjunctivitis)
nose bleed
sore, red mouth, swelling or irritation of the lining of the mouth, throat,
esophagus, stomach or intestines (mucosal inflammation/mucositis)
abnormal taste in mouth
dry mouth
increased sensitivity of the skin to sunlight
decrease in potassium in the blood
increased level of creatinine in your blood (blood creatinine increase), which
may be a sign of kidney damage
increased levels of substances in the blood produced by the liver
These side effects are considered uncommon (may affect up to 1 in 100 people):
• Fever with low white blood cell count (febrile neutropenia)
• Decrease in all types of blood cells (pancytopenia)
These side effects are considered rare (may affect up to 1 in 1000 people):
• Severe life-threatening infection due to low white cell counts (associated
with low blood pressure and possible organ failure (for example, heart, kidney
and/or liver) (neutropenic sepsis)
• Severe increase in blood pressure.
• A brain condition with symptoms including seizures, headache, confusion and
changes in vision
In addition to the above, the side effects below were reported by patients who
were prescribed niraparib by their doctors:
• Allergic reaction (hypersensitivity, including anaphylaxis).
• Life-threatening allergic reaction (such as difficulty breathing, rash,
localized swelling, such as tongue, throat or lips) (anaphylaxis)
• Confusion
• Disorientation
• Hallucination
• Impaired concentration, understanding, memory and thinking
• Inflammation of the (pneumonitis)
Niraparib belongs to the group known as PARP inhibitors. These class effects
are potential risks for the group of drugs, but have not yet been identified
as side effects for niraparib.
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML):
• PARP inhibitors may cause blood cancers known as myelodysplastic syndrome
(MDS) and acute myeloid leukemia (AML).
• MDS/AML, including cases with a fatal outcome have been reported in a small
number of patients who took niraparib or placebo (i.e., sugar pill). In 2
studies comparing niraparib to placebo, the likelihood of getting MDS/AML in
patients who took niraparib was similar to those in patients who took placebo.
Second Primary Malignancy:
• PARP inhibitors may also cause a new primary cancer (that is, a cancer other
than the one for which you have been treated). In 2 studies comparing niraparib
to placebo, the likelihood of getting a new primary cancer in patients who took
niraparib was similar to those in patients who took placebo.
Risks associated with study procedures
• Blood draws: mild pain, bruising, irritation or redness from the needle.
• CT scans: The cumulative radiation exposure from the tests is considered
small and is not likely to adversely affect the subject. However, the effects
of radiation add up over a lifetime. It is possible that having several of
these tests may add to your risk of injury or disease.
• MRI: Some people cannot have an MRI because they have some type of metal in
their body. For instance, if you have a heart pacemaker, artificial heart
valves, metal implants such as metal ear implants, bullet pieces, chemotherapy
or insulin pumps or any other metal such as metal clips or rings, they cannot
have an MRI. During this test, you will lie in a small closed area inside a
large magnetic tube. Some people are scared or anxious in small places
(claustrophobic). The MRI scanner makes loud banging noises while taking a
measurement, so either ear plugs or specially designed headphones will be used
to reduce the noise.
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Van Asch van Wijckstraat 55H
Amersfoort 3811 LP
NL
Listed location countries
Age
Inclusion criteria
Male or female, age 18 years and above.
Diagnosis of NSCLC
Advanced or metastatic NSCLC
Completion of 4-6 cycles of platinum-based standard of care first-line
induction chemotherapy with pembrolizumab
Participants must have SD, PR, or CR of their NSCLC per Investigator*s
assessment
ECOG performance status 0-1.
Life expectancy of at least 12 weeks.
Adequate organ and bone marrow function
Participants must submit FFPE tumor specimens
Toxicity from induction therapy must have recovered to a level of organ and
bone marrow function as defined by Inclusion Criteria #8 (see protocol) and no
ongoing toxicity with grade 3 or higher.
Able to swallow and retain orally administered study treatment.
Contraception guidelines for females and males should be followed
Exclusion criteria
Mixed small cell lung cancer or sarcomatoid variant NSCLC.
Received prior PARP inhibitor(s) in prior lines of treatment.
A systolic BP >140 mmHg or diastolic BP >90 mmHg.
A clinically significant gastrointestinal abnormalities that may alter
absorption.
Leptomeningeal disease, carcinomatous meningitis, symptomatic BM, or
radiographic signs of CNS hemorrhage.
Received colony-stimulating factors within 4 weeks prior to the first dose of
study treatment.
Active or previously documented autoimmune or inflammatory disorder
Receiving chronic systemic steroids (prednisone >20 mg per day).
Participants with asthma who require intermittent use of bronchodilators,
inhaled steroids, or local steroid injections would not be excluded from the
study.
Previously or currently participating in a treatment study with IP within 4
weeks of the first dose of standard of care first-line induction therapy.
Received prior systemic cytotoxic chemotherapy, biological therapy or hormonal
therapy for cancer, or received thoracic radiation therapy of >30 Gy within 6
months of the first dose of the start of standard of care first-line induction
therapy.
Received live vaccine within 30 days of planned start of study randomization.
Known hypersensitivity to the components of niraparib, placebo, or
pembrolizumab or their formulation excipients.
Major surgery within 4 weeks of starting the first dose of
study treatment or have not recovered from any effects of any major surgery.
Active concomitant malignancy that warrants systemic, biologic or hormonal
therapy.
Pregnant, breastfeeding or expecting to conceive children while receiving study
treatment and/or for up to 180 days after the last dose of study treatment.
Presence of hepatitis B or hepatitis C
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-508443-40-00 |
| EudraCT | EUCTR2020-002202-20-NL |
| CCMO | NL75207.100.20 |
| Other | www.gskclinicalstudyregister.com, nummer 213400 |